During aging, there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage, neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2, accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus, this model system is useful for exploring links between aging, oxidative damage, A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly, beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present, the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and;(2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses, treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease.